Project summary/abstract South Africa has approximately 7 million persons with HIV and 300 000 new TB cases a year, and disease treatment is complex, requiring prolonged multi-drug therapy. Cutaneous IM-ADRs occur in ~20% of all HIV-infected patients, and treatment-limiting severe cutaneous adverse drug reactions (SCAR) are both overrepresented and under-studied in Africa. The primary scientific objective of this K43 is to develop a well-defined cohort with specific clinical and immune phenotypes to define the genetic and mechanistic basis of SCAR associated with treatment of high burden diseases such as HIV and its co-morbidities including tuberculosis. The overall training objective of this K43 is to obtain theoretical and technical skills in advanced laboratory immunology that will prepare the PI to become a global leader in drug hypersensitivity science. Focal areas for mentorship and training include: i) Ex vivo assays to define drug-specific responses from peripheral blood ii) HLA-biology to identify risk allele(s), including cluster analysis, iii) Pharmaco- kinetics and genomics of culprit drug exposure and metabolism, and iv) Single cell T-cell receptor and RNA sequencing techniques, both bench and analysis components. Training areas are linked to the three study aims. Aim 1 is to define the unique clinical and immunological phenotypes of SCAR in HIV uninfected, HIV infected and TB patients with HIV co-infection in South Africa. A total of 250 SCAR cases and 500 matched controls to target drugs will be characterized using clinical tools, in vivo and drug provocation testing; and ex vivo assays such as ELISpot and flow cytometry to identify drug-specific T-cell responses. Aim 2 is to define pharmacogenomic risk factors in this cohort through high resolution HLA-typing and advanced genetic and pharmacological analyses, In Aim 3, we will investigate the hypothesis that a dominant or oligoclonal drug-specific T cell population (CD3+) exists at the site of acute tissue damage of these SCARs. We will use single cell TCR sequencing and RNAseq of activated and antigen driven CD8+ and/or CD4+ T cells from the skin in acute and recovery phases of SCAR. We will assemble a well-defined cohort of SCAR patients and controls and predict that we will define critical aspects of the epidemiology, pharmacogenomic and mechanistic basis of SCAR in high burden HIV and TB populations in Africa. This will have direct translation to SCAR in diverse treatment settings and translate into new ways to optimize treatment and prevention of SCAR in HIV-TB infected patients.